While Tamoxifen (Tam) has proven to be effective as a breast cancer prevention agent,Tam therapy only reduces the risk of developing breast cancer by ~50% in high risk women. Therefore, identification of biomarkers is essential to determine which women will benefit from Tam prevention. Recent studies suggest that rapid non-classical hormone signaling may play an important role in normal mammary gland homeostasis through stimulation of extra nuclear targets and co-activator recruitment. We observe in breast cytology specimens from high-risk women that ER expression is elevated in only 20% of mammary atypia and low ER expression in mammary atypia does not predict resistance to Tam prevention. We hypothesize that in women with mammary atypia, rapid non-classic signaling may play an important role regulating response to Tam prevention. PELP1 is a transcriptional nuclear activator of ER-signaling. Cytoplasmic expression of PELP1 in breast cancer cells triggers constitutive activation of AKT and results in Tam-resistance. Further, Dr. Seewaldt's laboratory has demonstrated that Tam promotes apoptosis through the coordinated regulation of AKT- phosphorylation. The objective of my current research is to determine if PELP1 localization predicts response to Tam. Here, I aim to test the hypothesis that cytoplasmic PELP1 promotes Tam-resistance, in part, through constitutive activation of AKT. The following Aims are proposed: 1) Does cytoplasmic localization of PELP1 in HMECs promote Tam-resistance through constitutive activation of Akt? 2) Does cytoplasmic PELP1 localization in atypical RPFNA cytological samples from high-risk women predict dysregulated AKT? 3) Does cytoplasmic PELP1 in atypical RPFNA predict cytological resistance to Tam prevention? PUBLIC HEALTH RELEVANCE: Currently there are no good biomarkers that predict which women will get breast cancer or respond to chemoprevention therapies. The objective of this proposal is to determine if cytoplasmic localization of PELP1 predicts resistance to tamoxifen chemoprevention in women at high-risk for developing breast cancer.